Epilepsy and other neurological disorders

CHAPTER 12

Epilepsy and other neurological disorders Gaetano Zaccara*, Filippo Sean Giorgi†, Fabio Giovannelli‡ *

Regional Health Agency of Tuscany, Florence, Italy Department of Clinical and Experimental Medicine, Section of Neurology, University of Pisa and Pisa University Hospital, Pisa, Italy ‡ Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Firenze, Italy †

Contents 1. Introduction 2. Cerebrovascular diseases 2.1 Treatment of seizures in cerebrovascular disorders 3. Infections of the central nervous system 3.1 Neurological complications of HIV infection 3.2 Treatment of seizures in infectious diseases of the CNS 4. Inflammatory diseases of the central nervous system 4.1 Immune-mediated encephalitis 4.2 Treatment of seizures in patients with immune-mediated encephalitis 4.3 Multiple sclerosis 5. Cerebral tumors 5.1 Treatment of seizures in patients with CNS tumors 6. Neurodegenerative disorders 6.1 Dementia 6.2 Parkinson’s disease 6.3 Other neurodegenerative disorders 7. Conclusions References Further reading

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Abbreviations AEDs AD ARV CNS CFS DRESS

antiepileptic drug Alzheimer’s disease antiretroviral central nervous system cerebrospinal fluid drug-related rash with eosinophilia and systemic symptoms

The Comorbidities of Epilepsy https://doi.org/10.1016/B978-0-12-814877-8.00012-X

© 2019 Elsevier Inc. All rights reserved.

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FTD HD LBD MRI MCI PD PET VaD

frontotemporal lobe degeneration Huntington’s disease Lewy body disease magnetic resonance imaging mild cognitive impairment Parkinson’s disease positron emission tomography vascular dementia

1. Introduction Comorbidity is a greater than coincidental association of two condition in the same individual [1]. In the case of neurologic conditions that occur in association with epilepsy, these may be a cause or a consequence of epilepsy and may precede, co-occur, or follow the diagnosis of epilepsy [2]. There are several explanations for the coexistence of epilepsy with other neurological diseases: (1) the association between epilepsy and the comorbid condition is a result of a bias, and there is not a true causal relationship (chance and artifactual comorbidity); (2) comorbid condition causes epilepsy via direct or indirect causal mechanisms (causative mechanisms); (3) mechanism of association is similar to the causative model, but the temporal sequence is reversed (epilepsy may start before the comorbid condition); (4) a confounding factor is a common cause both for epilepsy and the comorbid condition (shared risk factors); and (5) the two conditions can each cause the other (bidirectional effects) [3]. Recently, it has been suggested that in several conditions comorbid with epilepsy, a systemic dysfunction is in some way responsible for both diseases [4]. As a consequence of this hypothesis, a correct treatment of epilepsy should also include treatment of those dysfunctions that also cause comorbidities. In this chapter, the most important neurological diseases comorbid with epilepsy are described.

2. Cerebrovascular diseases In elderly people, cerebrovascular diseases constitute the most frequent cause of epilepsy [2], and several data indicate a complex relationship between these two diseases. Two, not mutually excluding, hypotheses have been proposed: both diseases are caused by a common factor and/or they are each a risk factor of the other (bidirectional effect). According to the time of their appearance after a stroke, there are two different types of seizures with very different pathophysiological mechanisms and prognosis. Early seizures, also called acute symptomatic seizures, occur within 7 days after stroke onset and are consequent to local metabolic disturbances associated with acute infarction. Late seizures, also called remote symptomatic or unprovoked seizures [3],

Epilepsy and other neurological disorders

occur after a silent period, which usually varies from a few months to several years [5], and originate from some injured brain areas where neuronal networks, due to structural modifications, have acquired the new property of becoming persistently hyperexcitable [6]. These different kinds of seizures are associated with different risks of seizure recurrence and require different treatment strategies. Overall, incidence of acute seizures in different studies varies between 3% and 13% [7] and is probably underestimated [8]. In addition, they are highly dependent on the characteristics of stroke with their prevalence being 2.4% and 4.8% after ischemic or hemorrhagic stroke, respectively. Among ischemic strokes, cardioembolic strokes have a higher risk compared to those associated with small or large vessel disease. The highest risk of early seizures is reported in patients with subarachnoid hemorrhage and venous cerebral thrombosis [7]. In a meta-analysis, intracerebral hemorrhage, cerebral infarction with hemorrhagic transformation, stroke severity, and alcoholism resulted significantly associated with a greater probability of early seizure occurrence [9]. Status epilepticus can be a relatively frequent acute complication of a stroke and is often underdiagnosed, although a closer EEG and clinical monitoring of such patients improve diagnosis. In a retrospective population study of patients admitted for intracerebral hemorrhage, it has been found that prevalence of diagnosis of status epilepticus increased from 1999 to 2011 [10]. As far as late or unprovoked poststroke seizures are concerned, it has been shown that cumulative risk of their appearance, in a large population-based study conducted over a period of 12 years following vascular episode, was 1.5% at 3 months, 3.5% at 1 year, 9% at 5 years, and 12.4% at 10 years [11]. Although risk of late seizures was also influenced by age, being higher in patients below 65 years of age, its main determinant was constituted by the anatomical characteristics of cerebral damage. Total anterior circulation infarct was associated with the greatest risk of poststroke epilepsy, while a progressive lower risk was observed with subarachnoid hemorrhage, primary intracerebral hemorrhage, partial anterior circulation infarct, lacunar infarct, and posterior circulation infarct. Two metaanalyses indicate that risk factors associated with late seizures following a stroke are cortical involvement and stroke severity [9, 12]. Small vessel diseases that may lead to deep infarcts and leukoaraiosis (white matter rarefaction) are also associated with an increased risk of late seizures [13]. While all these data show that vascular diseases are a strong risk factor for epilepsy, epilepsy may be a risk factor for stroke. In fact, it has been shown that epilepsy that starts in the elderly [14] as well as in adulthood [15] is associated with higher incidence of stroke. The explanation for these findings may be that both epilepsy and cerebrovascular diseases share similar risk factors. In fact, heart disease, hypertension, hyperlipidemia, diabetes, smoking, and lower rates of exercise [14] are known risk factors both for stroke and epilepsy. In addition, epilepsy seems to predispose to

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venous thromboembolism, which is three times more frequent in patients with epilepsy than that among people with migraine [16].

2.1 Treatment of seizures in cerebrovascular disorders Several evidences indicate that, in patients with cerebrovascular diseases, antiepileptic drug (AED) treatment, mainly with first-generation AEDs, may be associated with a poor rehabilitation outcome and may also worsen progression of atherosclerosis. Typical dosedependent motor or cognitive adverse effects of several AEDs are more frequently observed in patients with stroke. In addition, early generation AEDs cause subtle metabolic alterations, which may constitute a predisposing factor for atherosclerosis [17]. These agents may have negative effects on lipids and other metabolic parameters associated with a higher risk of cerebrovascular diseases. Cholesterol (HDL, LDL, and VLDL), triglycerides, and lipoproteins can be affected by carbamazepine and phenobarbital [17]. Homocysteine concentration, an independent risk factor for atherosclerosis, as a consequence of enzyme induction, has been found increased in adult epileptic patients treated with phenytoin or phenobarbital. A symptomatic carbamazepine or oxcarbazepine-induced hyponatremia is more frequent in patients with vascular diseases who are often elderly and receiving several other sodium level-decreasing drugs. Finally, some AEDs (especially gabapentin, pregabalin, vigabatrin, and valproate) may cause an increase in body weight, which is an important risk factor for cardiovascular and cerebrovascular diseases [17]. A further negative effect of several first-generation AEDs in patients with cerebrovascular diseases is the induction of metabolism of many drugs used for treatment of atherosclerosis and prevention of thrombosis [18, 19]. For example, new anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban may be ineffective or less effective when associated with enzyme-inducing drugs with severe possible consequences, such as cardiac emboli and stroke. In Table 1, most relevant drug interactions between AEDs and drugs pertaining to the ATC coding system as class B (blood and blood-forming organs) and class C (cardiovascular system) are reported. The effect of cardio and cerebrovascular agents on epilepsy should also be considered. Recently, concerns have been raised that treatment of acute stroke with recombinant tissue plasminogen activator, which is the only approved thrombolytic agent, might increase the risk of seizures (including early and late seizures). However, in a systematic review of 792 patients with ischemic stroke who received this treatment, rates of seizures were similar in patients treated or not treated with this agent [20]. Based on all these considerations, the decision of starting or not starting a treatment for seizures is of strategic importance. Since there is no clinical evidence of an antiepileptogenic effect for any AED, all guidelines do not recommend primary prevention of

Table 1 Relevant drug interactions between agents pertaining to ATC code B (blood and blood-forming organs) and C (cardiovascular system) and antiepileptic drugs Drug-altering Kind of interaction metabolism Drug whose metabolism is altered

Phenobartbital, carbamazepine, phenytoin Phenobartbital, carbamazepine, phenytoin

Inhibition of the serum concentration of AEDs

Diltiazem, ticlopidine, verapamil Levetiracetam

Induction of P-gp

Apixaban, bemiparin, bivalirudin, clopidogrel, dabigatran, dalteparin, edoxaban, enoxaparin, heparin, rivaroxaban, ticagrelor, warfarin Amiodarone, amlodipine, atenolol, atorvastatina, bisoprolol, bosentan, digoxin, diltiazem, disopyramide, dopamine, dronedarone, eplerenone, felodipine, fluvastatine, isradipine, ivabradine, labetalol, lacidipine, lercanidipine, losartan, lovastatine, macitentan, metoprolol, mexiletine, nebivolol, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, propafenone, ranolazine, rosuvastatine, simvastatine, tolvaptan, valsartan, verapamil Carbamazepine, phenytoin

Dabigatran, apixaban, edoxaban, rivaroxaban

This list should not be regarded as exhaustive. Only those interactions considered clinically significant are reported. From References Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord 2014;16(4):409–31 and Medscape. Available from: https://reference.medscape.com/drug-interactionchecker [last accessed 18 April 2018].

Epilepsy and other neurological disorders

Induction of metabolism of drugs coded B (blood and blood-forming organs agents) in the ATC classification system Induction of metabolism of drugs coded C in the ATC (cardiovasvular agents)

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epilepsy in patients with stroke or other vascular diseases [21, 22]. Interestingly, experimental studies show that several drugs used for the treatment of vascular diseases might have the property to interfere with the process of epileptogenesis. Statins for example, have been found to reduce the risk of late seizures due to antiinflammatory effects and prevention of blood-brain barrier injury [23]. In a few cases, although high-quality evidence for routine anticonvulsant use in subarachnoid hemorrhage or cerebral venous thrombosis is lacking, short-term prophylactic antiepileptic therapy in the immediate posthemorrhagic period is sometimes used [24, 25], based on the argument that seizures or status epilepticus in such acutely ill patients could lead to additional injury [21, 26]. After a seizure, drug treatment may be indicated for prevention of further seizures, although different treatment strategies should be planned for early or late seizures. In the case of early seizures, a treatment can be administered to reduce the risk of seizure relapse in the short term and should be discontinued shortly [27] while, after a late seizure, a long-term antiepileptic treatment is required [6]. Patient with vascular diseases are often elderly and with typical age-related pharmacokinetic changes (reduction in hepatic and renal clearance and lower protein binding) that may lead to higher brain concentration and toxicity of some drugs. Hence, in those cases in which AED treatment is appropriate, low starting doses and a slow titration should be adopted. As large clinical studies have not yet been carried out in this special population of patients, there is no consensus regarding the most appropriate AED that should be used as a first-line drug. However, old generation AEDs have an unfavorable kinetic profile, a potential harmful impact on motor and cognitive functions and negative effects on progression of atherosclerosis. Levetiracetam, lamotrigine, lacosamide, and also topiramate and zonisamide should have a similar efficacy but should be safer than traditional AEDs and should be preferred.

3. Infections of the central nervous system Central nervous system (CNS) infections and infestations, particularly in resource-poor settings, are among the most common preventable risk factors for acute seizures and symptomatic epilepsy worldwide [28]. They include viral, bacterial, protozoan, fungal, and prion disease (Creutzfeldt-Jakob). Seizures may occur during all these acute CNS infections, may be the only presenting symptom of infection such as neurocysticercosis, or may appear after a period of latency. Even in this case, similarly to vascular diseases, early seizures, which may occur in up to 30% of CNS infections soon after the time of a systemic insult, are not considered spontaneous seizures and are thought to be mechanistically different from consequential chronic epilepsy. Early seizures may lead to status epilepticus, which in this case has often a worse prognosis than that due to other etiologies.

Epilepsy and other neurological disorders

Spontaneous recurrent late seizures result from neuronal loss and gliosis, molecular and structural reorganization, and epigenetic reprogramming, which are related to the infectious agent, the severity of brain injury, age, and several other factors. Risk of these late seizures in developed countries is between 6.8% and 8.3%, while it is higher in resource-poor settings [29]. Some antimicrobials may have a proconvulsant effect. In the general population, evidence for the association between antibiotic drugs and seizures as adverse events is low to very low [30]. However, in patients with CNS infections, this risk may be much higher, even though, in such cases, it is almost impossible to establish a cause-effect relationship because of the concomitant effect of the concurrent disease [31]. Antimicrobials considered most often proconvulsant are: antimalarials, carbapenems, cephalosporins, unsubstituted penicillins, and ciprofloxacin in combination. Also, isoniazid overdose has been associated with seizures [18, 30]. Therefore, some precautions should be taken for the selection of the appropriate antimicrobial in patients with CNS infections. A drug with the lowest epileptogenic potential should be selected, dosage should be adjusted according to the degree of possible renal impairment for drugs eliminated by kidneys, and in patients with special predispositions, monitoring of serum antimicrobial levels may be advocated. It should be noted that seizures observed during cephalosporin treatment are often reported to be nonconvulsive, and EEG may be necessary for diagnosis of such complications [30]. There are also interactions between AEDs and infectious diseases. In patients with these diseases, some idiosyncratic adverse drug reactions are more frequently observed. There is evidence for a complex relationship between viral infections and a serious adverse drug reaction, namely drug-related rash with eosinophilia and systemic symptoms (DRESS), which has been associated with aromatic AEDs (phenytoin, phenobarbital, carbamazepine, lamotrigine, oxcarbazepine, eslicarbazepine) [32]. In fact, in the serum of patients with AED-induced DRESS, 2–3 weeks after the onset of the idiosyncratic reaction, a rise has been observed in human herpes virus (HHV)-6 DNA levels, and it has been suggested that this virus might play a pathogenic role in this condition. Reactivation of HHV-7, cytomegalovirus, and/or Epstein-Barr virus may also play a role in such adverse drug reactions [33]. On the other hand, several AEDs have anti-inflammatory properties and, for this reason, might affect immune defense. Recently, in a metaanalysis of 127 randomized clinical trials with 16 AEDs, a mild increased risk of infection has been reported for topiramate and for levetiracetam and brivaracetam when pooled together [34]. It may be reasonable to hypothesize that these AEDs might have a weak facilitating effect for infectious diseases. Finally, drug interactions between antimicrobials and AEDs are frequent. For example, serum concentration of itraconazole can be reduced more than tenfold by enzymeinducing AEDs. Macrolide antibiotics increase drug levels of carbamazepine with

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Table 2 Most relevant drug interactions between ATC drugs coded J (antiinfectives for systemic use) and antiepileptic dugs Drug whose metabolism is Drugs that alter drug levels altered

Antimicrobials whose metabolism can be stimulated by AEDs

Enzyme-inducing AEDs, most notably carbamazepine, phenytoin, phenobarbital, and primidone

Antimicrobials that may increase the serum concentration of AEDs

Clarithromycin, erythromycin, fluconazole, isoniazid, itraconazole, ketoconazole, metronidazole, ritonavir, troleandomycin, voriconazole Chloramphenicol, fluconazole, isoniazid, miconazole, sulfaphenazole Chloramphenicol Erythromycin, isoniazid Ketoconazole Clarithromycin Imipenem, meropenem, ertapenem, doripenem Rifampicin

Antimicrobials that may reduce serum levels of AEDs

Albendazole, chloramphenicol, doxycycline, efavirenz, indinavir, itraconazole, lopinavir, metronidazole, nevirapine, posiconazole, praziquantel, rifampicin, ritonavir, saquinavir, voriconazole Carbamazepine

Phenytoin

Phenobarbital Valproate Clobazam Oxcarbazepine Valproic acid Lamotrigine

See legend of Table 1.

consequent toxicity. Meropenem or other carbapenem antibiotics induce metabolism of valproate with consequent loss of efficacy and withdrawal seizures [18]. In Table 2, most relevant drug interactions between AEDs and antimicrobials are reported.

3.1 Neurological complications of HIV infection HIV prevalence is increasing worldwide mostly because people on antiretroviral therapy are living longer, although new infections are decreasing [35]. Evidence of neurologic involvement has been observed as early as 3 months after HIV infection and extends across all the course of the disease. Prevalence of HIV-associated neurocognitive disorder increases with disease progression and includes asymptomatic neurocognitive impairment, mild neurocognitive disorder, and an advanced form of HIV-associated dementia. Seizures are frequently observed in people affected by this infective disease and may be consequent to a variety of mechanisms, including vulnerability to CNS opportunistic

Epilepsy and other neurological disorders

infections, neuronal damage induced by HIV replication within the CNS, and metabolic disturbances [35]. However, after the introduction of a combination of antiretroviral therapy for treatment of the disease, their prevalence has declined from 17% to 6%, which testify that seizures are generally a consequence of the progression of the disease [35]. Also in the case of HIV infection, as in other viral diseases, aromatic AEDs are associated with a higher risk of immunomediated adverse reaction when administrated in such patients [33]. For example, skin rash caused by phenytoin is more common in HIV-infected patients even though such patients are typically anergic and expected to be less prone to immune-mediated adverse reactions. For this reason, special attention should be paid when using aromatic AEDs in these patients. It has also been suggested that valproate may increase viral replication in HIV-infected patients [36]. Since effective HIV treatment requires lifelong treatment with at least three antiretroviral (ARV) drugs, possible interactions between these agents and coadministered AEDs are very important. It should be considered that in these patients, AEDs are also used for conditions other than epilepsy, such as painful neuropathies and psychiatric conditions. Interactions of greatest concern relate to the P450 system enzyme induction effects of the old-generation AEDs. Phenobarbital, carbamazepine, and phenytoin, which are still most often used in low- and middle-income countries where drug options may be limited, are expected to induce metabolism of nonnucleotide reverse transcriptase inhibitors and protease inhibitors, which are also metabolized by the P450 system. This interaction may lead to clinical disease progression and development of ARV drug resistance. Additional interactions of ARV drugs with AEDs are those characterized by induction of metabolism of AEDs by ARV drugs and inhibition of metabolism of ARV drugs by valproate or stiripentol. The most important examples of these interactions are a lopinavir/ritonavir plasma level decrease induced by phenytoin, a dramatic 16-fold reduction in blood levels of indinavir induced by carbamazepine, inhibition of zidovuline metabolism by valproate, and a 50% decrease in lamotrigine levels by ritonavir/atazanavir [35]. In several developing countries where phenobarbital is the only available antiepileptic treatment, these interactions are a critical problem. Risk of failure of HIV antiretroviral therapy and the consequent increase in HIV resistance to antiretroviral drugs often lead to the decision of avoiding treatment of seizures [37].

3.2 Treatment of seizures in infectious diseases of the CNS In patients with infective disease of CNS, epilepsy may present with several acute seizures or even status epilepticus. In these patients, intravenous administration of a benzodiazepine may be required, and especially in patients with established status epilepticus, AEDs must be administered through intravenous route. Formulations for intravenous use are available for

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four AEDs (phenytoin, phenobarbital, levetiracetam, lacosamide). Although phenytoin is the only AED whose summary of product characteristics reports the indication for treatment of status epilepticus, this drug is not easy to use and is a strong enzymatic inducer, which may interact with several drugs used for treatment of patients with status epilepticus [38]. Levetiracetam, valproic acid, or even lacosamide may be preferable. In regards to oral treatment, special attention should be given for the selection of AEDs not interacting with antimicrobial drugs and with a low risk of idiosyncratic adverse reactions [18, 33].

4. Inflammatory diseases of the central nervous system In the case of comorbidity between epilepsy and inflammatory diseases of CNS, inflammation causes acute seizures and epilepsy via direct or indirect causal mechanisms. However, there are also some bidirectional mechanisms in this case.

4.1 Immune-mediated encephalitis Awareness is growing that immune-mediated epilepsy may constitute a common cause of refractory, apparently cryptogenic epilepsy. Between 11% and 35% of all refractory epilepsies of undefined etiology may have an autoimmune etiology [39]. Unfortunately, epilepsy associated with autoimmune encephalitis remains underdiagnosed, mainly because these patients do not present with a well-defined clinical syndrome. Autoimmune epilepsy should be suspected when epilepsy begins with acute or subacute highly frequent seizures with variable semiologies (particularly after the third decade of life), presence of multifocal seizures on EEG, initial presentation with status epilepticus, or history of autoimmunity or neoplasm. Evidence in support of diagnosis includes inflammatory cerebrospinal fluid (CSF) findings (pleocytosis, elevated IgG index, and/or oligoclonal bands) and magnetic resonance imaging (MRI) findings suggestive of inflammation (typically, T2 hyperintensity in the mesial temporal structures often with a bilateral involvement). Simultaneous testing of both serum and CSF for the presence of antibodies targeting intracellular antigens or neuronal cell surface proteins is essential for diagnosis, although a negative result does not exclude a case of autoimmune epilepsy [39]. Diagnosis of possible autoimmune epilepsy can still be done if there is a clinical response to immunotherapy [40].

4.2 Treatment of seizures in patients with immune-mediated encephalitis Seizures associated with autoimmune encephalitis are characteristically refractory to treatment with AEDs. Seizure freedom can be achieved only in 10% of patients on AED monotherapy, while <15% will have a 50% reduction in seizure frequency [41]. In addition, specific

Epilepsy and other neurological disorders

antibody syndromes may strongly predispose patients to the development of particular adverse drug reactions. For example, oxcarbazepine and carbamazepine may more frequently cause or aggravate hyponatremia in patients with antibodies to the voltage-gated potassium channel complex, and cutaneous adverse effects of aromatic AEDs are observed in up to 50% of patients with LG1 antibodies [40]. No single AED is specifically recommended for the treatment of autoimmune epilepsy. It has been alleged that sodium channel blockers (e.g., carbamazepine, oxcarbazepine, lacosamide, lamotrigine, and phenytoin) are of a certain efficacy [42]. It has also been speculated that some AEDs may exert some positive immunomodulatory effects altering serum levels of interleukins and tumor necrosis factor-α [43]. Experimental findings show that levetiracetam and the newest brivaracetam may have protective and anti-inflammatory effects, modulating production of plasma TNF-α and antioxidant capacity [44]. Mechanism of action of these agents seems to be related with their binding with SV2A protein, which is expressed in neurons but also in other cell types including human CD8 + T lymphocytes. It has been shown that levetiracetam has inhibitory effects on the function of these lymphocytes [45]. However, AEDs are not the mainstay of therapy for treatment of autoimmune encephalitis. Corticosteroids, intravenous immunoglobulin, and plasmapheresis are considered first-line agent immunotherapies for treatment of patients with autoimmune epilepsy, whereas more specific immunosuppressive agents, such as monoclonal antibodies (mainly rituximab), are considered second-line agents [40]. Some patients may need immunosuppressant agents (cyclophosphamide mycophenolate). Also in this case, it should be remembered that metabolism of corticosteroids and of several immunosuppressive agents is strongly induced by phenobarbital, phenytoin, and carbamazepine. Therefore, enzyme-inducing AEDs should be avoided [18].

4.3 Multiple sclerosis Multiple sclerosis, the most common chronic immune-mediated disorder affecting CNS, is characterized by inflammation and destruction of myelin sheaths of neurons and has a wide range of signs and symptoms. About 2.3 million people are affected by this disease in the world, with rates varying widely in different regions and among different populations [46]. The occurrence of epilepsy during the course of multiple sclerosis has an annual incidence of 2.28% and a prevalence of 3.09% and suggests that the association of epilepsy and multiple sclerosis is more common than expected by chance [46]. Seizures can occur at any time during the disease and have also been described as the presenting symptom of the disease. Since epileptogenesis must necessarily involve the cortex, a special role in the pathogenesis of epilepsy in such disease should be played by pure intracortical lesions [47]. Interferons, which are used in the treatment of this disease, have been considered proconvulsant [48].

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With regard to treatment of seizures, in the context of an acute relapse, seizures are generally self-limiting and do not require treatment, whereas recurrence of seizures unrelated to relapse should be treated. Clinically important drug interactions between drugs used for chronic treatment of multiple sclerosis and AEDs have not been observed [19]. Impact on motor and cognitive functions, such as fatigue, vertigo, ataxia, diplopia, and cognitive slowing, which are typical of several AEDs, might worsen symptoms of the disease and also mimic disease activity. Although no treatment guidelines are available for treatment of epilepsy in patients with multiple sclerosis, new-generation AEDs with less severe specific motor and cognitive adverse effects should be preferred.

5. Cerebral tumors Comorbidity between epilepsy and cancer are discussed in detail in Chapter 9. Although the incidence of brain tumors as a cause of epilepsy accounts for only 4% of patients with epilepsy, seizures are relatively frequent in both primary and metastatic tumors. Approximately 30%–50% of patients with cerebral tumors will have seizures as a first sign of tumor and an additional 10%–30% will experience a seizure during the course of disease [49]. Seizure risk depends on type and location of tumor [50]. As a general rule, slowgrowing tumors, particularly gangliogliomas and dysembryoplastic neuroepithelial tumors, are associated with the highest rates of seizures while high-grade tumors have lower risk. Patients with metastatic brain lesions experience seizures less frequently than those with primary tumors. Incidence of seizures also varies among different metastatic masses being as high as 67% in metastatic melanoma. In addition, cortical involvement is more frequently associated with seizures while white matter, infratentorial, and sellar tumors are less often associated with seizures [51]. In regards to location, frontal, parietal, and temporal tumors, particularly those involving the mesial temporal lobe, insula, and other paralimbic structures are associated with higher rates of seizures than occipital tumors [51]. Mechanisms of epileptogenesis vary among different tumor types. While in lowgrade lesions this process is consequent to slowly developing focal abnormalities by vascular or mechanical changes that may isolate brain regions, in high-grade lesions tissue damage is mainly consequent to necrosis and hemosiderin deposition. In general, epileptic foci do originate from that portion of altered tissue that is between lesional and adjacent normal cortex and can also be at a certain distance from the tumor border. Peritumoral changes alter the permeability of vascular supply leading to breakdown of the blood-brain barrier and possible edema. Loss of balance between excitatory and inhibitory transmission [52], such as alteration of glutamate extracellular concentrations in astrocytes, dysfunction of adenosine-mediated neurotransmission, and alterations of

Epilepsy and other neurological disorders

gap junctions, take place in this area and have been found more compromised in low-grade gliomas than in high-grade gliomas [53]. Finally, seizures may not only be the direct consequence of tumor but can also be secondary to infection of the brain, which may result from immunosuppressive effects of chemotherapy or radiation necrosis [17].

5.1 Treatment of seizures in patients with CNS tumors In patients who have never had seizures, routine prophylactic use of AEDs is not recommended. Several systematic analyses of literature and clinical studies have shown that a prophylactic treatment with phenytoin, phenobarbital, or valproate does not reduce risk of a first seizure but significantly increases risk of adverse effects [54, 55]. Furthermore, AEDs should be withdrawn 1 week after surgery in those patients who received such drugs for prevention of acute symptomatic seizures [56]. After a first unprovoked seizure, a patient with brain tumor should be treated with AEDs [57] although in this case, the choice of the first AED is critical because of a series of concerns. Idiosyncratic adverse effects of AEDs are more frequently observed in this population of patients. For example, risk of carbamazepine-induced aplastic anemia is increased in patients receiving chemotherapy, which depresses the bone marrow, and radiotherapy facilitates the appearance of serious and life-threatening cutaneous adverse reactions caused by aromatic AEDs [51]. Epilepsies caused by brain tumors are more often drug resistant. Seizure freedom after a first AED treatment is observed in about 40% of patients, which is lower than that found in the overall population of epileptic patients. This finding has been explained by overexpression of proteins involved in multidrug resistance, reduced receptor sensitivity, or a wide epileptogenic area [55]. Concerning drug tolerability, it should be considered that patients with brain tumors and consequent neurological damages may be more prone to both motor and cognitive drug-induced adverse effects [56]. However, by far the most important issue is the effect of the coadministered AED on antineoplastic drug efficacy and disease progression. There is increasing awareness that pharmacokinetic interactions between antineoplastic agents and AEDs may have important clinical consequences. Enzyme-inducing AEDs, such as carbamazepine, phenytoin, and barbiturates, enhance the metabolic clearance and make less effective or even ineffective many concomitantly administered anticancer medications and also corticosteroids, which are often prescribed in these patients. Some studies show that overall survival of patients with glioblastoma multiforme is shorter in those patients receiving enzyme-inducing AEDs and this finding has been attributed to a lower efficacy of antineoplastic drugs [58]. With regards to valproic acid, which is an enzymatic inhibitor, it has been reported that coadministration of this agent with temozolomide and other anticancer agents may lead to an increased survival but also to more frequent adverse effects,

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such as thrombocytopenia and leukopenia [59, 60]. The improved prognosis in such patients has been explained by valproic acid’s ability to exert a mild inhibition of clearance of these drugs but also by a direct anticancer effect of valproate, which inhibits angiogenesis and induces cell differentiation and growth arrest of tumor cells through inhibition of histone deacetylase [60]. Increased hematologic toxicity observed with valproate in these patients can be consequent to an increased toxic effect on platelet function exerted by both valproate and antineoplastic agents or to metabolic inhibition of anticancer with consequent toxic levels of these agents [60]. A number of interactions whereby anticancer agents can increase or decrease the serum concentrations of AEDs have also been reported [60]. In Table 3 are reported the most important pharmacokinetic interactions between AEDs and drugs used in patients with brain tumors. All studies aimed at assessing AED efficacy in patients with brain tumors typically consist of retrospective or small prospective case series, which are heterogeneous concerning tumor histology, disease phase, kind of anticancer treatment, and seizure frequency. Therefore, treatment choices are largely determined by physicians’ opinions and by individual patient characteristics. AEDs that are frequently selected as first-line therapy include second-generation nonenzyme-inducing AEDs lamotrigine, lacosamide levetiracetam, oxcarbazepine, topiramate, and zonisamide, all of which are approved as initial monotherapy for focal seizures. Polytherapy with more than an AED can be considered in those patients who have an unsatisfactory response to the initially prescribed drug at full doses, although there are cases in which persistence of some minor seizures can be inevitable and should be accepted instead as causing intolerable adverse effects. Surgical resection of the tumor, radiotherapy, and chemotherapy, which are treatment modalities for control of tumor growth, are also generally associated with seizure improvement. On the contrary, seizure recurrence in a patient with previously well-controlled seizures may be caused by recurrence or progression of the tumor, side effects of cancer therapy (radionecrosis), or infectious or metabolic encephalopathy [60].

6. Neurodegenerative disorders 6.1 Dementia The comorbidity between epilepsy and dementia is quite common among the elderly. The reason for such coexistence may be that both neurological conditions are frequent, although several lines of evidence support higher incidence of epilepsy among demented patients and especially in patients with Alzheimer’s disease (AD). The main causes of dementia are degenerative and vascular, and the two conditions often coexist in the same subject [61]. Strategic infarcts are a frequent cause of vascular dementia (VaD), and these lesions also represent a major cause of acquired epilepsy in the elderly.

Table 3 Relevant drug interactions between antineoplastic and immunosuppressant agents and AEDs Drugs that alter drug Kind of interaction levels Drug whose metabolism is altered

Phenobartbital, carbamazepine, phenytoin

Induction of metabolism of steroids that may be used in patients with brain tumor Inhibition of metabolism of antineoplastic and immunosuppressant agents by AEDs Inhibition of metabolism of AEDs

Phenobartbital, carbamazepine, phenytoin Valproate

5-Fluorouracil, tacrolimus, tamoxifen

Abiraterone, afatinib, axitinib, bendamustine, bexarotene, bleomicine, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, carmustine, cisplatin, crizotinib, cyclophosphamide, cyclosporine, dabrafenib, dasatinib, docetaxel, doxorubicin, erlotinib, etoposide, everolimus, fluorouracil, gefitinib, ifosfamide, imatinib, irinotecan, exemestan, lapatinib, methotrexate, mitoxantrone, mycophenolate, nilotinib, pazopanib, pirfenidon, pomalidomide, praclitaxel, procarbazin, regorafenib, sirolimus, sorafenib, sunitinib, tacrolimus, tamoxifen, temsirolimus, teniposide, thiotepa, topotecan, toremifen, trabectedin, vandetanib, vemurafenib, vinblastine, vincristine, vindesine, vinorelbinea Cortisol, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolonea Cisplatinum, etoposide, nitrosoureas, temozolomide, temsirolimus Phenytoin

See legend of Table 1. a In this list, metabolism of each drug was induced by at least one of enzyme-inducing antiepileptic drug.

Epilepsy and other neurological disorders

Induction of metabolism of antineoplastic and immunosuppressant agents

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The link between VaD and epilepsy has been explored trough a population-based nested case-control analysis from a large database of UK general practitioners. It has been shown that incidence rate of epilepsy diagnosis within 2 years from the diagnosis of VaD was more than nine folds higher than among age-matched controls and also higher than in AD (where it was 7.1 folds higher than controls). In the nested analysis, prevalence of dementia (mainly VaD), among a sample of patients with incident epilepsy after 65 years, was one third of the sample [62]. 6.1.1 Alzheimer’s disease The main forms of neurodegenerative dementia are represented by (AD), frontotemporal lobe degeneration (FTD) and Lewy body disease (LBD). Among them, AD is by far the most prevalent, especially in patients above 65 years of age [63].Higher incidence of myoclonus among demented patients, especially in those with a more advanced disease, has been emphasized in old studies [64, 65]. Concerning other seizure types, their precise incidence has not yet been established, as it varies dramatically among different studies [66, 67]. A reason for such discrepancy may be that in earlier studies in which epilepsy was evaluated in AD patients, diagnostic criteria of dementia were different from the ones currently in use. In fact, nowadays the diagnosis of AD is based not only on clinical but also on objective criteria, such as MRI and fluoro-desoxyglucose positron emission tomography (PET), and, more recently, it is supported by biomarkers, such as amyloid levels (either assessed by PET or by CSF analysis) or Tau and Phospho-Tau (at present only in CSF) [68]. Another main limitation of several analyses, those from both clinicbased databases [69] and large community public datasets [70], is that they were retrospective. In all cases, the database from which epilepsy data were extracted had not been designed to specifically evaluate the occurrence of seizures. Thus, only clear, previous tonic-clonic seizures were likely to be reported by relatives of the patients, while more subtle phenomena were easily missed. Complex partial seizures, which are represented by definition by consciousness impairment, can be very difficult to identify in these patients, unless they are also accompanied by a clear motor behavior. Even in the latter scenario, however, repetitive stereotyped behaviors accompanying complex partial seizures can be difficult to discriminate from repetitive behaviors often occurring in demented patients, especially at late dementia stages. The reasons listed in the previous paragraph concur to underestimate the occurrence of seizures in patients with dementia/cognitive impairment. In any case, in an interesting recent retrospective analysis it was observed that earlier onset of AD is associated with higher incidence of concomitant epilepsy [71]. Furthermore, most seizures in these patients were complex partial and nonconvulsive. In most of the studies on seizures and AD, EEG data were generally not available or available only in few patients [72]. In one study, performed in a memory clinic, EEG was consecutively collected in a very large cohort of patients (almost 1700) affected by either

Epilepsy and other neurological disorders

mild cognitive impairment (MCI), AD, or “other dementia,” and evaluated for the occurrence of epileptiform discharges. These were present in approximately 2% of patients with AD or MCI and in 1% of patients with other forms of dementia; in approximately 20% of patients with epileptiform activity, new seizures occurred at follow up; finally, epileptiform activity was more often present in younger patients [72]. A consistently higher percentage of subclinical discharges (>40% of AD patients without prior history of seizures, which was significantly higher than in the group of age-matched controls) was found in a prospective study on 33 patients with more sophisticated techniques of analysis [73]. In conclusion, it is widely accepted that the occurrence of epilepsy among AD is significantly higher than in the normal population and that it might be particularly prevalent in patients with early AD (and especially familial AD) and younger age; seizures are more frequently focal limbic and, at later stages, myoclonic. Interesting data on the relationship between neuropathogical alterations observed in AD and seizures come from studies in preclinical AD models. Mice transgenic for amyloid pathogenic mutation show a significantly reduced threshold to electrographic seizures before the onset of the AD-related pathologic changes [74]. More recently, it has been also observed that early administration of AEDs in these mice significantly attenuates interictal activity [75] and attenuate cognitive and pathological alterations [76]. Degeneration of the noradrenergic nucleus locus coeruleus seems also to be involved in the pathogenesis of dementia and seizures. Degeneration of such brain nucleus may precede by decades the onset of dementia and seems to play a pathogenic role in the development dementia [76]. On the other hand, noradrenaline has anticonvulsant effects in almost all epilepsy model tested [77]. 6.1.1.1 Treatment of epilepsy in Alzheimer’s disease

The choice of the best treatment of epilepsy in patients with dementia shares several aspects with treatment indications in elderly, in general, and, concerning VaD, the same principles for cerebrovascular diseases (paragraph 2 of this chapter) can be applied. For treatment of epilepsy in AD, there are also other specific potential aspects to consider [78]. It has been shown that valproate may worsen cognitive functions, and data show that, in rare cases, it may increase brain atrophy rate [79]. For these reasons, this agent should not be a first-line choice even though it has been used for control of some behavioral disturbances in patients with dementia [80]. Evidences from uncontrolled studies suggest a potential significant efficacy of levetiracetam [81]. Similarly, lamotrigine has also been shown to be similarly effective in demented patients with epilepsy as confirmed by retrospective studies [71]. Despite the potential positive cognitive effects concerning levetiracetam, one should keep in

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mind the potential psychiatric effects (including agitation), which have been repeatedly described for this drug. However, in favor of levetiracetam and lamotrigine choice, among MCI or patients at early stages of AD, are also the promising recent observations in experimental models of AD (as previously described in this chapter). Finally, epileptic subjects with dementia are at risk of drug-induced seizures, as they are often exposed to antipsychotics, some of which are significantly proconvulsant [82]. Interactions between antidepressant and antipsychotic drugs are described in other sections of this book (see Chapters 16 and 17). Some interactions are described between acetylcholinesterase inhibitors, used to improve cognition in demented patients, and AEDs. Metabolism of both donepezil and galantamine is induced by old generation AEDs (phenobarbital, phenytoin, carbamazepine), which often require a dose increase. Instead, rivastigmine, which is without hepatic metabolism by the CYP-450 system, and memantine have no interactions with AEDs. 6.1.2 Other forms of degenerative dementias There are only rough estimates of epilepsy incidence in LBD, which are based mainly on retrospective analyses; a higher incidence of seizures among patients with LBD than in the general population has been estimated, almost similar to AD [83] or even higher [84]. Furthermore, cortical myoclonus might be particularly frequent in these subjects, affecting >20% of them [85], and its occurrence might be related to specific cortical pathological features. Even though detailed analysis of the most prevalent types of seizures among LBD patients is not available, one should keep in mind that one of the core diagnostic features of LBD is the fluctuation of vigilance during the day, which is often quite abrupt and might make difficult to identify focal seizures that also might be featured mainly by attention/vigilance reduction. It has been documented by several studies that EEG often shows focal sharp waves [85]. There are no specific studies assessing the effects of specific AEDs in LBD patients with seizures. Interestingly, a recent controlled clinical trial provided some evidences of a good profile in terms of cognitive profile and tolerability of zonisamide administered together with L-DOPA in patients with LBD, with even an additive effect on parkinsonism as compared with L-DOPA [86]. FTD is a term describing dementia involving mainly the frontal and temporal lobe, asymmetrically, but under this term different causes of dementia as well as different etiologies are included [87]; thus, coexistence of FTD with other disorders is likely to vary significantly depending on the subtype. A recent retrospective study in a relatively large series of patients showed that FTD is less associated to new-onset seizures than AD and LBD but more than the general population [84].

Epilepsy and other neurological disorders

6.2 Parkinson’s disease Epilepsy and Parkinson’s disease (PD) have been considered, in general, nonrelated. Actually, the two conditions have been considered by several neurologists even reciprocally exclusive, that is, the occurrence of one condition associated with a lower incidence of the other. This opinion dates back to the early decades of the last century, after a few observations of patients with postinfective parkinsonism in which development of PD signs was associated with a decrease of seizure frequency [88]. However, postencephalitic syndrome does not correspond neuropathologically to idiopathic parkinsonism (i.e., PD), and even the opposite has been claimed to occur, namely an improvement of PD signs after seizure onset [87]. In any case, both scenarios were merely based on anecdotal reports and have not been studied in large population-based studies. There are, however, interesting data obtained in patients’ cohorts, such as the large analysis in a group of PD patients assessed in a tertiary neurology center [89]. In this study, it has been shown that, among 1215 PD patients, the incidence of epilepsy was lower than expected in age-matched general population samples. Of incidental interest for the present review, (but nonetheless intriguing), it has also been assessed that the occurrence of status epilepticus occurred in PD twice as frequently as in the general population. However, a large epidemiological analysis [2] suggested a slightly increased coexistence of PD among patients with epilepsy. The latter study was based on part of the large patients’ UK General Practice Research Database, which included data on more than one million people. Among those with a coded diagnosis of epilepsy, 4% had a coexistent diagnosis of PD. However, several biases may weaken these data. In particular diagnosis of PD, which is mainly based on clinical judgment, was not confirmed by a specialist. Experimental data do not bring more evidences to the link between epilepsy and PD. In a model of PD in mice, changes as to seizure incidence or threshold of different types of experimental seizures have not been found [90]. Moderate interactions characterized by induction of metabolism of drugs used for treatment of PD are described between L-DOPA, ropinirole, rasagiline, and phenytoin, while selegiline and ropinirole are induced by carbamazepine [19]. Finally, valproate in elderly patients often has a tremorigen effect [91], which might further complicate its use, especially in PD patients.

6.3 Other neurodegenerative disorders Concerning Huntington’s disease (HD), there are several evidences for a high incidence of seizures in patients with early-onset HD [91], while recent data confirm the common belief that prevalence of seizures in patients with adult-onset HD is similar to that of age-matched population [92]. It should be noted that patients with HD are often treated with antipsychotics, which have potential proconvulsant effects [82].

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Finally, no information on seizures has been reported in large casistics of subjects with corticobasal degeneration [93] or progressive sopranuclear palsy, although early reports signaled seizures in a nonnegligible percentage of patients [94].

7. Conclusions Today, much more than in the past, epilepsy is comorbid with several neurological diseases, and all these diseases may be caused by a common etiologic factor [4] or can reciprocally influence each the other. In all cases, therapeutic strategy should carefully consider these aspects.

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